Adjuvant Transarterial Chemoembolization Plus Immunotherapy for Huge Hepatocellular Carcinoma: A Propensity Score Matching Cohort Study

Figures & data

Table 1 Baseline Characteristics of the AIT Group Compared with the at Group Before and After PSM

Parameters	Before PSM		p value	After PSM		p value
	AIT Group (n=83)	AT Group (n=211)		AIT Group (n=77)	AT Group (n=77)
Age (years)			0.038			1.000
≤65	80 (96.4%)	187 (88.6%)		74 (96.1%)	73 (94.8%)
>65	3 (3.6%)	24 (11.4%)		3 (3.9%)	4 (5.2%)
Sex			0.529			1.000
Male	76 (91.6%)	188 (89.1%)		70 (90.9%)	70 (90.9%)
Female	7 (8.4%)	23 (10.9%)		7 (9.1%)	7 (9.1%)
Basic liver disease			0.541			0.677
No	5 (6.0%)	11 (5.2%)		4 (5.2%)	2 (2.6%)
Yes	78 (94.0%)	200 (94.8%)		73 (94.8%)	75 (97.4%)
HBV	77 (92.8%)	191 (90.5%)		72 (93.5%)	72 (93.5%)
Others	1 (1.2%)	9 (4.3%)		1 (1.3%)	3 (3.9%)
HBV load (IU/mL)			0.069			0.331
<1000	21 (29.6%)	78 (41.9%)		19 (28.4%)	26 (37.7%)
≥1000	50 (70.4%)	108 (58.1%)		48 (71.6%)	43 (62.3%)
Child-Pugh class			0.848			0.754
A	78 (94.0%)	197 (93.4%)		72 (93.5%)	71 (92.2%)
B	5 (6.0%)	14 (6.6%)		5 (6.5%)	6 (7.8%)
ALT (U/L)			0.938			0.713
≤40	61 (73.5%)	156 (73.9%)		56 (72.7%)	58 (75.3%)
>40	22 (26.5%)	55 (26.1%)		21 (27.3%)	19 (24.7%)
AST (U/L)			0.892			0.420
≤40	39 (47.0%)	101 (47.9%)		35 (45.5%)	40 (51.9%)
>40	44 (53.0%)	110 (52.1%)		42 (54.5%)	37 (48.1%)
Total bilirubin (μmol/L)			0.249			1.000
≤17.1	64 (77.1%)	175 (82.9%)		61 (79.2%)	61 (79.2%)
>17.1	19 (22.9%)	36 (17.1%)		16 (20.8%)	16 (20.8%)
Albumin (g/L)			0.428			1.000
≥35.0	63 (75.9%)	169 (80.1%)		58 (75.3%)	58 (75.3%)
<35.0	20 (24.1%)	42 (19.9%)		29 (24.7%)	29 (24.7%)
Platelets (*10^9/L)			0.943			1.000
≥100	80 (96.4%)	203 (96.2%)		74 (96.1%)	74 (96.1%)
<100	3 (3.6%)	8 (3.8%)		3 (3.9%)	3 (3.9%)
NLR			0.413			0.814
≤ 5	72 (86.7%)	190 (90.0%)		67 (87.0%)	66 (85.7%)
>5	11 (13.3%)	21 (10.0%)		10 (13.0%)	11 (14.3%)
PT (s)			0.612			1.000
≤14.5	69 (83.1%)	170 (80.6%)		64 (83.1%)	64 (83.1%)
>14.5	14 (16.9%)	41 (19.4%)		13 (16.9%)	13 (16.9%)
AFP (ng/mL)			0.260			0.870
≤400	37 (44.6%)	79 (37.4%)		33 (42.9%)	32 (41.6%)
>400	46 (55.4%)	132 (62.6%)		44 (57.1%)	45 (58.4%)
Tumor size (cm)	12.0 (10.4–15.0)	11.8 (10.2–14.0)	0.286	12.0 (10.4–15.0)	12.0 (10.8–14.0)	0.628
BCLC stage			0.077			0.424
A	49 (59.0%)	153 (72.5%)		48 (62.3%)	46 (59.7%)
B	13 (15.7%)	24 (11.4%)		13 (16.9%)	9 (11.7%)
C	21 (25.3%)	34 (16.1%)		16 (20.8%)	22 (28.6%)
Macrovascular invasion			0.042			0.253
No	63 (75.9%)	181 (85.8%)		62 (80.5%)	56 (72.7%)
Yes	20 (24.1%)	34 (14.2%)		15 (19.5%)	21 (27.3%)
Multiple tumors			0.349			0.832
No	68 (81.9%)	182 (86.3%)		64 (83.1%)	63 (81.8%)
Yes	15 (18.1%)	29 (13.7%)		13 (16.9%)	14 (18.2%)
Satellites			0.010			0.741
No	49 (59.0%)	157 (74.4%)		48 (62.3%)	46 (59.7%)
Yes	34 (41.0%)	54 (25.6%)		29 (37.7%)	31 (40.3%)
MVI			<0.001			1.000
No	25 (30.1%)	113 (53.6%)		25 (32.5%)	25 (32.5%)
Yes	58 (69.9%)	98 (46.4%)		52 (67.5%)	52 (67.5%)
Ruptured tumor			0.598			0.797
No	73 (88.0%)	190 (90.0%)		69 (89.6%)	68 (88.3%)
Yes	10 (12.0%)	21 (10.0%)		8 (10.4%)	9 (11.7%)
E-S grade			0.420			0.427
I+II	19 (22.9%)	58 (27.5%)		18 (23.4%)	14 (18.2%)
III+IV	64 (77.1%)	153 (72.5%)		59 (76.6%)	63 (81.8%)
Intrahepatic blood transfusion			0.118			0.362
No	65 (78.3%)	146 (69.2%)		59 (76.6%)	54 (70.1%)
Yes	18 (21.7%)	65 (30.8%)		18 (23.4%)	23 (29.9%)
Hepatectomy type			0.126			0.321
Minor*	30 (36.1%)	97 (46.0%)		27 (35.1%)	33 (42.9%)
Major	53 (63.9%)	114 (54.0%)		50 (64.9%)	44 (57.1%)
Laparoscopic hepatectomy			0.471			0.400
No	78 (94.0%)	193 (91.5%)		72 (93.5%)	68 (88.3%)
Yes	5 (6.0%)	18 (8.5%)		5 (6.5%)	9 (11.7%)
Operative time (minutes)	275 (243,329)	269 (228,315)	0.279	275 (245,333)	287 (248,329)	0.747
Bleeding volume (mL)	400 (200,800)	400 (200,800)	0.524	450 (200,875)	400 (200,600)	0.518

Notes: Bold text means P < 0.05. Minor hepatectomy defined as ≤ 2 Couinaud segments.

Abbreviations: PSM, propensity-score matching; HBV, hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; NLR, neutrophil-to-lymphocyte ratio; PT, prothrombin time; AFP, alpha-fetoprotein; BCLC stage, Barcelona Clinic Liver Cancer stage; MVI, microvascular invasion; E-S grade, Edmonson-Steiner grade.

Figure 1 Flowchart of patients’ enrollment for comparison.

Abbreviation: PSM, propensity score matching.

Table 2 Recurrence and Survival Data Before and After PSM

Parameters	Before PSM		p value	After PSM		p value
	AIT Group (n=83)	AT Group (n=211)		AIT Group (n=77)	AT Group (n=77)
Recurrence	50 (60.2%)	155 (73.5%)	0.026	46 (59.7%)	65 (84.4%)	0.001
RFS			0.035			<0.001
Median RFS (months)	11.7 (8.0,19.3)	6.9 (5.6,8.9)		11.7 (8.0,19.3)	3.9 (3.3,7.5)
1-year RFS	48.7%	33.9%		49.9%	24.7%
2-year RFS	35.8%	25.1%		35.7%	15.5%
Mortality	24 (28.9%)	98 (46.4%)	0.006	20 (26.0%)	48 (62.3%)	<0.001
OS			0.025			<0.001
Median OS (months)	NR	NR		NR	12.6 (8.7,22.5)
1-year OS	83.7%	67.1%		83.6%	50.6%
2-year OS	63.1%	51.8%		66.9%	36.8%
Recurrence type			0.331			0.253
Intrahepatic	33 (66.0%)	86 (55.5%)		30 (65.2%)	33 (50.8%)
Extrahepatic	6 (12.0%)	18 (11.6%)		5 (10.9%)	7 (10.8%)
Intra + extrahepatic	11 (22.0%)	51 (32.9%)		11 (23.9%)	25 (38.5%)
Recurrence in margin	9 (18.0%)	30 (19.4%)	0.832	6 (13.0%)	14 (21.9%)	0.236
Extrahepatic metastasis	17 (34.0%)	69 (44.5%)	0.190	16 (34.8%)	32 (49.2%)	0.130
Lung	12	42		12	21
Lymph node	2	10		2	6
Adrenal	1	4		0	2
Bone	1	1		0	1
Brain	1	2		1	1
Others	3	11		2	7
BCLC stage in recurrence			0.167			0.375
0	1 (2.0%)	14 (9.0%)		1 (2.2%)	5 (7.7%)
A	4 (8.0%)	18 (11.6%)		3 (6.5%)	5 (7.7%)
B	22 (44.0%)	44 (28.4%)		20 (43.5%)	18 (27.7%)
C	21 (42.0%)	75 (48.4%)		20 (43.5%)	75 (53.8%)
D	2 (4.0%)	4 (2.6%)		2 (4.3%)	4 (3.1%)
Recurrence treatment			0.419			0.199
Refuse	6 (12.0%)	26 (16.8%)		5 (10.9%)	13 (20.0%)
Accept	44 (88.0%)	129 (83.2%)		41 (89.1%)	52 (80.0%)
Treatment			<0.001			<0.001
Repeat resection	2 (4.5%)	10 (7.8%)		2 (4.9%)	5 (9.6%)
MWA	2 (4.5%)	18 (14.0%)		2 (4.9%)	5 (9.6%)
TACE	4 (9.1%)	61 (47.3%)		4 (9.8%)	30 (57.7%)
Systemic therapy	9 (20.5%)	14 (10.9%)		8 (19.5%)	5 (9.6%)
Combined therapy*	26 (59.1%)	20 (15.5%)		24 (58.5%)	3 (5.8%)
Chemotherapy or radiotherapy	1 (2.3%)	6 (4.7%)		1 (2.4%)	4 (7.7%)

Note: Bold text means P < 0.05.

Abbreviations: PSM, propensity-score matching; RFS, recurrence free survival; OS, overall survival; BCLC stage, Barcelona Clinic Liver Cancer stage; MWA, microwave ablation; TACE, transarterial chemoembolization; *, systemic therapy combined with microwave ablation or transarterial chemoembolization.

Figure 2 Comparison of RFS (A) and OS (B) between the AIT group and AT group after PSM.

Table 3 Adverse Events in Regard to Immunotherapy

Adverse Events^#	Grades 1/2	Grade 3/4
Total patients	29 (34.9%)	5 (6.0%)
Rash/Pruritus	7 (8.4%)	1 (1.2%)
Fatigue	3 (3.6%)	0 (0.0%)
Diarrhoea	4 (4.8%)	1 (1.2%)
Myalgia/Myositis	1 (1.2%)	0 (0.0%)
Nausea/vomiting	2 (2.4%)	1 (1.2%)
Allergic reaction	2 (2.4%)	0 (0.0%)
Neutropenia	6 (6.5%)	0 (0.0%)
Increased ALT or AST	4 (4.8%)	1 (1.2%)
Increased total bilirubin	0 (0.0%)	1 (1.2%)
Carditis	1 (1.2%)	0 (0.0%)
Albuminuria	1 (1.2%)	0 (0.0%)
Pain	2 (2.4%)	0 (0.0%)
Upper gastrointestinal bleeding	1 (1.2%)	0 (0.0%)
Decreased platelets	6 (6.5%)	0 (0.0%)
Anemia	2 (2.4%)	0 (0.0%)
Edema	3 (3.6%)	0 (0.0%)
Hypothyroidism	5 (6.0%)	1 (1.2%)
Peripheral nerve injury	1 (1.2%)	0 (0.0%)
Hypertension	2 (2.4%)	0 (0.0%)

Note: ^#Transient adverse events during TACE treatment were not recorded.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 4 Univariate and Multivariate Analysis of RFS and OS for Huge HCC After PSM

Variable	RFS						OS
	Univariate			Multivariate			Univariate			Multivariate
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Age (years, > 65 vs ≤65)	0.978	0.429~2.228	0.957				0.855	0.269~2.723	0.792
Sex (female vs male)	0.936	0.488~1.792	0.841				0.618	0.248~1.537	0.300
Basic liver disease (yes vs no)	2.200	0.698~6.935	0.178				21.697	0.163~2882.372	0.163
HBV load (IU/mL,≥1000 vs <1000)	1.223	0.800~1.869	0.353				1.072	0.629~1.826	0.798
Child-Pugh class (B vs A)	1.375	0.812~2.326	0.236				1.609	0.695~3.725	0.266
ALT (U/L, >40 vs ≤40)	1.326	0.875~2.009	0.183				1.161	0.677~1.990	0.587
AST (U/L, >40 vs ≤40)	1.306	0.899~1.898	0.162				1.070	0.664~1.723	0.782
Total bilirubin (μmol/L, >17.1 vs ≤17.1)	1.041	0.658~1.648	0.864				1.026	0.570~1.847	0.993
NLR (>5 vs ≤5)	1.110	0.644~1.913	0.707				1.782	0.955~3.327	0.070
Albumin (g/L, ≥35.0 vs <35.0)	0.852	0.555~1.308	0.464				0.874	0.499~1.533	0.640
AFP (ng/mL, >400 vs ≤400)	1.715	1.167~2.522	0.006	1.451	0.957~2.200	0.080	2.173	1.290~3.663	0.004	1.704	0.959~3.025	0.069
Tumor diameter (cm)	1.054	0.984~1.128	0.135				1.009	0.922~1.104	0.843
Macrovascular invasion (yes vs no)	1.824	1.202~2.768	0.005	1.703	1.091~2.656	0.019	2.132	1.289~3.527	0.003	1.742	1.038~2.926	0.036
Multiple tumors (yes vs no)	1.863	1.183~2.934	0.007	1.672	1.009~2.770	0.046	1.265	0.691~2.317	0.446
Satellites (yes vs no)	2.189	1.499~3.197	<0.001	1.719	1.112~2.657	0.015	2.230	1.381~3.602	0.001	2.197	1.295~3.726	0.004
MVI (yes vs no)	1.078	0.722~1.609	0.714				1.020	0.613~1.695	0.940
Ruptured tumor (yes vs no)	1.193	0.655~2.173	0.564				2.249	1.178~4.292	0.014	1.938	0.922~4.076	0.081
E-S grade (III+IV vs I+II)	1.580	0.964~2.592	0.070				1.472	0.772~2.807	0.241
Adjuvant treatment (AIT vs AT)	0.507	0.347~0.741	<0.001	0.445	0.302~0.656	<0.001	0.344	0.204~0.581	<0.001	0.319	0.188~0.541	<0.001
Intraoperative blood transfusion (yes or no)	1.411	0.936~2.129	0.101				2.027	1.237~3.321	0.005	2.046	1.194~3.505	0.009

Note: Bold text means P < 0.05.

Abbreviations: RFS, recurrence free survival; OS, overall survival; HCC, hepatocellular carcinoma; PSM, propensity score match; HBV, hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; NLR, neutrophil-to-lymphocyte ratio; AFP, alpha-fetoprotein; MVI, microvascular invasion; E-S grade, Edmonson-Steiner grade.

Figure 3 Continued.

Figure 3 Forest plot for subgroup survival analysis for RFS (A) and OS (B).

Abbreviations: AFP, alpha-fetoprotein; E-S, Edmonson-Steiner; MVI, microvascular invasion.

Data Sharing Statement

The data that support the findings of this study are not publicly available due to privacy or ethical restrictions but are available on request from the corresponding author.